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Zmienność Żołądkowej Dehydrogenazy Alkoholowej a Ryzyko Uzależnienia Od Alkoholu Variation in Gastric Alcohol Dehydrogenase and the Risk of Alcohol Dependence

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Zmienność Żołądkowej Dehydrogenazy Alkoholowej a Ryzyko Uzależnienia Od Alkoholu Variation in Gastric Alcohol Dehydrogenase and the Risk of Alcohol Dependence Arch Med Sąd Kryminol 2016; 66 (3): 172–181 DOI: https://doi.org/10.5114/amsik.2016.66401 archiwum medycyny sądowej i kryminologii Praca poglądowa Review paper Paulina Całka, Marzanna Ciesielka, Grzegorz Buszewicz, Grzegorz Teresiński Zmienność żołądkowej dehydrogenazy alkoholowej a ryzyko uzależnienia od alkoholu Variation in gastric alcohol dehydrogenase and the risk of alcohol dependence 1Katedra i Zakład Medycyny Sądowej Uniwersytetu Medycznego w Lublinie 2Studium Medycyny Molekularnej 1Chair and Department of Forensic Medicine, Medical University in Lublin 2Postgraduate School of Molecular Medicine Streszczenie Uzależnienie od alkoholu stanowi problem zarówno medyczny, jak i społeczno-ekonomiczny. Jest zaliczane do chorób o charakterze wieloczynnikowym, czyli takich, za które odpowiadają relacje gen–gen oraz gen–środo- wisko. Wieloośrodkowe badania nad genetycznym podłożem alkoholizmu podkreślają znaczenie genów kodu- jących enzymy szlaku rozkładu etanolu w organizmie ludzkim, szczególnie dehydrogenazy alkoholowej (ADH) w rozwoju choroby. Z pięciu klas dehydrogenaz alkoholowych związek z uzależnieniem od alkoholu wykazują izoen- zymy klasy I i IV. Klasa IV jest szczególnie interesująca ze względu na jej występowanie w górnym odcinku przewodu pokarmowego, głównie w żołądku. Nie wykazano aktywności tego enzymu w wątrobie. Polimorfizm pojedynczych nu- kleotydów (SNP) genu kodującego tę klasę, czyli ADH7, wpływa na jej aktywność utleniającą etanol w świetle żołądka i tym samym na metabolizm pierwszego przejścia ( FPM) tej substancji. Opublikowane wyniki różnych ośrodków ba- dawczych pokazują, że konkretne zmiany typu SNP w genie ADH7 mają odmienne znaczenie dla ryzyka uzależnienia od alkoholu w zależności od badanej populacji. Słowa kluczowe: ADH7, alkoholizm, metabolizm pierwszego przejścia. Abstract Alcohol dependence is both a medical and socioeconomic problem. The disease is multifactorial, i.e. its development is attributable to gene-gene and gene-environment interactions. Multi-centre studies investigating the genetic back- ground of alcoholism stress the role of genes encoding enzymes of the ethanol decomposition pathway in the human body, particularly alcohol dehydrogenase (ADH), in the development of alcohol dependence. Among five classes of alcohol dehydrogenases, class I and IV isoenzymes have been found to be associated with alcohol dependence. Class IV is of particular interest due to its occurrence in the upper gastrointestinal tract, mainly in the stomach. No activity of the enzyme has been demonstrated in the liver. Single nucleotide polymorphism (SNP) of the gene encoding ADH class IV (ADH7) affects its ethanol-oxidizing activity in the gastric lumen, thereby influencing the first-pass metabo- lism (FPM) of the substance. The findings published by various research centres have demonstrated that specific SNP changes in the ADH7 gene are of different significance for the risk of alcohol dependence according to the population studied. Key words: ADH7, alcoholism, first-pass metabolism. Copyright © 2016 by PTMSiK Arch Med Sąd Kryminol 2016; vol. 66: 172–181 Wprowadzenie Introduction Alkohol etylowy jest spożywany w nieomal każ- Ethyl alcohol is consumed in almost every soci- dym społeczeństwie, a jego popularność wynika głów- ety, and its popularity is mainly attributable to the nie z faktu, że jest łatwy w produkcji, najmniej tok- fact that it is easy to produce and characterized by syczny spośród alkoholi alifatycznych oraz wykazuje the least toxic and the most prominent “psychoac- największe spośród nich działanie „psychoaktywne” tive” effects of all aliphatic alcohols [1]. Alcohol de- [1]. Uzależnienie od alkoholu to powszechna i złożona pendence is a widespread and complex disease [2] choroba [2], która stanowi poważny problem zarówno which represents both a medical and socioeconomic społeczno-ekonomiczny, jak i medyczny. Na skłonność problem. The propensity for alcohol dependence re- do alkoholizmu składa się połączenie efektów wielu sults from a combination of multiple factors includ- czynników, takich jak: geny związane ze szlakami me- ing genes related to alcohol metabolism pathways, tabolizmu alkoholu, elementy środowiskowe i obec- environmental components and coexisting mental ność współwystępujących zaburzeń psychicznych [3]. disorders [3]. W 2015 r. opublikowano wyniki projektu „Epi- The EZOP (“Epidemiology of mental disorders demiologia zaburzeń psychiatrycznych i dostępność and access to mental health care”) study published psychiatrycznej opieki zdrowotnej” (EZOP), które in 2015 shows that over 2% of the Polish adult pop- wykazały, że ponad 2% osób dorosłych w Polsce speł- ulation meet the criteria of alcohol dependence. nia kryteria uzależnienia od alkoholu. Nadmierne Excessive consumption of alcoholic beverages is as- spożycie napojów alkoholowych wiąże się w znacz- sociated to a considerable extent with the mortali- nym stopniu z umieralnością Polaków, włączając w to ty rates in the Polish population including cases of przypadki samobójstw oraz utonięć w stanie intok- suicide and drowning while intoxicated with alcohol sykacji alkoholem [4]. Według danych Państwowej [4]. Data compiled by the State Agency for the Pre- Agencji Rozwiązywania Problemów Alkoholowych vention of Alcohol-Related Problems (PARPA) indi- (PARPA) średnie spożycie alkoholu w przeliczeniu cate that the average per capita alcohol consumption na jednego mieszkańca systematycznie wzrasta (dane in Poland is growing steadily (2014 data) [5]. The re- z 2014 r.) [5]. Amerykański, wieloośrodkowy projekt sults obtained in the U.S. multi-centre research proj- badawczy zajmujący się ustalaniem genetycznego ect investigating the genetic background of alcohol podłoża uzależnienia od alkoholu (COGA) przyniósł dependence (Collaborative Study on the Genetics of wyniki wskazujące na związek występowania alko- Alcoholism – COGA) reveal a correlation between holizmu z regionem na chromosomie 4 skupionym alcoholism and a chromosome 4 region located near w pobliżu klastra genów dehydrogenazy alkoholowej, the gene cluster encoding alcohol dehydrogenase – enzymu odpowiedzialnego za rozkład etanolu [2]. an enzyme responsible for ethanol decomposition Celem niniejszej pracy jest przedstawienie znaczenia [2]. The present study aims to outline the role of żołądkowego metabolizmu alkoholu etylowego oraz gastric metabolism of ethyl alcohol and its effect on jego wpływu na biodostępność etanolu. the bioavailability of ethanol. Eliminacja etanolu w organizmie ludzkim Ethanol elimination from the body Dystrybucja alkoholu w organizmie zachodzi The distribution of alcohol in the body takes place poprzez wodę zawartą w tkankach. Dzięki właści- through water contained in body tissues. Thanks to wościom fizycznym etanol może przenikać przez its physical properties ethanol is able to pass through błony biologiczne zgodnie z gradientem stężeń [6], biological membranes according to the concentra- a największy odsetek wchłaniania spożytego alko- tion gradient [6], and in terms of percentages ingest- holu zachodzi w jelitach (ok. 75%), ale także w żo- ed alcohol is absorbed primarily in the intestines (ca. łądku (ok. 25%) [7, 8]. 75%), but also in the stomach (ca. 25%) [7, 8]. Spożyty alkohol ulega reakcjom katabolicznym, Following ingestion, alcohol undergoes catabolic które w ostatnim etapie powodują jego rozkład na reactions which in the final stage result in its decom- związki nietoksyczne, a głównym miejscem meta- position into non-toxic compounds. The principal Archiwum Medycyny Sądowej i Kryminologii Archives of Forensic Medicine and Criminology 173 Paulina Całka, Marzanna Ciesielka, Grzegorz Buszewicz, Grzegorz Teresiński Zmienność żołądkowej dehydrogenazy alkoholowej a ryzyko uzależnienia od alkoholu ADH – dehydrogenaza alkoholowa; g-ADH – „żołądkowa” dehydrogenaza alkoholowa; MEOS – mikrosomalny układ utleniania etanolu; XO – oksydaza ksantynowa; ALDH – dehydrogenaza aldehydowa ADH – alcohol dehydrogenase; g-ADH – gastric alcohol dehydrogenase; MEOS – the microsomal ethanol oxidizing system; XO – xanthine oxidase; ALDH – aldehyde dehydrogenase Ryc. 1. Szlaki eliminacji etanolu po podaniu doustnym w organizmie ludzkim (opracowano na podstawie [10] z modyfikacjami) Fig. 1. Pathways of ethanol elimination after oral alcohol intake (based on [10] with modifications) Archiwum Medycyny Sądowej i Kryminologii 174 Archives of Forensic Medicine and Criminology Arch Med Sąd Kryminol 2016; vol. 66: 172–181 bolizmu etanolu jest wątroba. Odkrycie Julkunena, site of ethanol metabolism is the liver. When Julkunen który zauważył, że u szczurów po podaniu doust- discovered that a considerable amount of ethanol ad- nym znaczna ilość etanolu nie weszła do krwiobie- ministered orally to rats did not enter the circulation, gu, zapoczątkowało badania nad metabolizmem research was undertaken to determine the metabo- tego związku poza wątrobą. Wykazał on, że część lism of the compound outside the liver. The research- spożytego alkoholu może być metabolizowana przez er showed that in rats some ingested alcohol can be śluzówkę żołądka szczurów [9]. Zmienia to pogląd metabolized by the gastric mucosa [9]. The finding na zjawisko określane mianem metabolizmu pierw- changes the traditional view of the first-pass metabo- szego przejścia (FPM), który definiowany jest jako lism (FPM) which is defined as the difference between różnica pomiędzy ilością substancji spożytą a ilością the amount of a substance that is ingested and the trafiającą do krwiobiegu [10]. Pierwotnie uważano,
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